Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia
Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection ar...
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| Format: | Article |
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Elsevier
2011-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996111001896 |
| _version_ | 1818611092688994304 |
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| author | Rhonda Souvenir Nancy Fathali Robert P. Ostrowski Tim Lekic John H. Zhang Jiping Tang |
| author_facet | Rhonda Souvenir Nancy Fathali Robert P. Ostrowski Tim Lekic John H. Zhang Jiping Tang |
| author_sort | Rhonda Souvenir |
| collection | DOAJ |
| description | Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. This study investigated if tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and its upstream regulator signaling molecule Janus kinase-2 (JAK-2) are critical in EPO-induced neuroprotection. Hypoxia ischemia (HI) was modeled in-vitro by oxygen and glucose deprivation (OGD) and in-vivo by a modified version of Rice–Vannucci model of HI in 10-day-old rat pups.EPO treated cells were exposed to AG490, an inhibitor of JAK-2 or TIMP-1 neutralizing antibody for 2 h with OGD. Cell death, phosphorylation of JAK-2 and signal transducers and activators of transcription protein-3 (STAT-3), TIMP-1 expression, and matrix metalloproteinase-9 (MMP-9) activity were measured and compared with normoxic group. Hypoxic ischemic animals were treated one hour following HI and evaluated 48 h after. Our data showed that EPO significantly increased cell survival, associated with increased TIMP-1 activity, phosphorylation of JAK-2and STAT-3, and decreased MMP-9 activity in vivo and in vitro. EPO's protective effects were reversed by inhibition of JAK-2 or TIMP-1 in both models. We concluded that JAK-2, STAT-3 and TIMP-1 are key mediators of EPO-induced neuroprotection during hypoxia ischemia injury. |
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| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T15:24:50Z |
| publishDate | 2011-10-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj.art-d754f06ec0d140f69dcab4ad567afeb22022-12-21T22:26:32ZengElsevierNeurobiology of Disease1095-953X2011-10-014412837Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemiaRhonda Souvenir0Nancy Fathali1Robert P. Ostrowski2Tim Lekic3John H. Zhang4Jiping Tang5Division of Microbiology and Molecular Genetics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Division of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADivision of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADivision of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADivision of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADivision of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADivision of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Corresponding author. Fax: +1 909 558 0119.Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. This study investigated if tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and its upstream regulator signaling molecule Janus kinase-2 (JAK-2) are critical in EPO-induced neuroprotection. Hypoxia ischemia (HI) was modeled in-vitro by oxygen and glucose deprivation (OGD) and in-vivo by a modified version of Rice–Vannucci model of HI in 10-day-old rat pups.EPO treated cells were exposed to AG490, an inhibitor of JAK-2 or TIMP-1 neutralizing antibody for 2 h with OGD. Cell death, phosphorylation of JAK-2 and signal transducers and activators of transcription protein-3 (STAT-3), TIMP-1 expression, and matrix metalloproteinase-9 (MMP-9) activity were measured and compared with normoxic group. Hypoxic ischemic animals were treated one hour following HI and evaluated 48 h after. Our data showed that EPO significantly increased cell survival, associated with increased TIMP-1 activity, phosphorylation of JAK-2and STAT-3, and decreased MMP-9 activity in vivo and in vitro. EPO's protective effects were reversed by inhibition of JAK-2 or TIMP-1 in both models. We concluded that JAK-2, STAT-3 and TIMP-1 are key mediators of EPO-induced neuroprotection during hypoxia ischemia injury.http://www.sciencedirect.com/science/article/pii/S0969996111001896JAK-2STAT-3TIMP-1EPONeonatal HI |
| spellingShingle | Rhonda Souvenir Nancy Fathali Robert P. Ostrowski Tim Lekic John H. Zhang Jiping Tang Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia Neurobiology of Disease JAK-2 STAT-3 TIMP-1 EPO Neonatal HI |
| title | Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia |
| title_full | Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia |
| title_fullStr | Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia |
| title_full_unstemmed | Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia |
| title_short | Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia |
| title_sort | tissue inhibitor of matrix metalloproteinase 1 mediates erythropoietin induced neuroprotection in hypoxia ischemia |
| topic | JAK-2 STAT-3 TIMP-1 EPO Neonatal HI |
| url | http://www.sciencedirect.com/science/article/pii/S0969996111001896 |
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